Disitamab vedotin (DV) plus toripalimab (Tor) and chemotherapy (C)/trastuzumab (Tra) as first-line (1L) treatment of patients (pts) with HER2-expressing locally advanced or metastatic (la/m) gastric cancer.
Lin Shen, Zhi Peng, Changzheng Li, Linzhi Lu, Xiang Wang, Jun Zhang, Yanqiao Zhang, Ting Deng, Meili Sun, Dongyan Cai, Yin Jin, Hong Zong, Feng Ye, Huiting Xu, Mingjun Zhang, Jianzhi Liu, Dan Feng, Jianmin Fang
Abstract
LBA4012 Background: DV+T showed encouraging efficacy with manageable safety for pts with HER2-expressing gastric or gastroesophageal junction (G/GEJ) cancer in the second- and later-line setting in a phase 1 trial (Wang et al, eClinicalMedicine, 2024). Here, we first report the efficacy and safety of 1L DV+Tor+C/Tra in pts with HER2-postive or HER2-low la/m G/GEJ cancer from the randomized phase 2 part of a seamless phase 2/3 trial. Methods: Pts with previously untreated HER2-positive (IHC 3+, or IHC 2+/FISH+) la/m G/GEJ cancer were randomized (1:1:1) to receive DV (2.5 mg/kg, Q2W) + Tor (3.0 mg/kg, Q2W) + CAPOX (oxaliplatin [OX]: 130 mg/m 2 , day 1; capecitabine [CAP]: 1000 mg/m 2 , days 1-14; Q3W) (experimental group [EG] 1), or DV + Tor +Tra (staring dose of 8 mg/kg followed by 6 mg/kg, Q3W) (EG2), or Tor + Tra + CAPOX (control group [CG] 1). For pts with HER2-low (IHC 1+, or IHC 2+/FISH-) la/m G/GEJ cancer, they were initially randomized (1:1) to receive DV (2.5 mg/kg) + Tor + CAPOX (EG1), or Tor + CAPOX (CG1) in stage 1; based on the safety data from stage 1, stage 2 was designed to randomize pts (1:1:1) to receive DV (2.5 mg/kg) + Tor + CAPOX (reduced dose: OX 100 mg/m 2 ; CAP 750 mg/m 2 ) (EG2), or DV (2.0 mg/kg) + Tor + CAPOX (reduced dose) (EG3), or Tor + CAPOX (CG2). The primary endpoint was objective response rate (ORR). Results: By date cutoff (Feb 7, 2025), 51 HER2-positive pts (mostly being HER2 IHC 3+) and 93 HER2-low pts (mostly being HER2 IHC 1+) were enrolled. In HER2-positive pts, superior ORR of 82.4% was observed in EG2. In HER2-low pts, the ORR was 70.8% in EG1 and the hazard ratio (HR) for PFS was 0.67 compared to CG1 in stage 1, which favored the experimental group; the highest ORR was 76.9% in EG2 in stage 2. Main outcomes are listed in the Table. Data will be updated during presentation. Conclusions: In pts with HER2-positive la/m G/GEJ cancer, DV + Tor + Tra demonstrated a superior ORR, offering a potential chemo-free treatment option. In pts with HER2-low la/m G/GEJ cancer, DV + Tor + CAPOX showed superior ORR and PFS with a manageable safety profile; lowering the CAPOX dose improved tolerability of the combination therapy while maintaining high efficacy. Clinical trial information: NCT05980481 . HER2-positive pts HER2-low pts / Stage 1 Stage 2 (dose optimization) EG1 (n=18) EG2 (n=17) CG1 (n=16) EG1 (n=25) CG1 (n=23) EG2 (n=14) EG3 (n=15) CG2 (n=16) Confirmed ORR*, % (95% CI) 66.7(41.0-86.7) 82.4(56.6-96.2) 68.8(41.3-89.0) 70.8(48.9-87.4) 47.8(26.8-69.4) 76.9(46.2-95.0) 60.0(32.3-83.7) 46.7(21.3-73.4) Median PFS follow-up, months 11.2 12.2 12.2 9.7 5.6 Median PFS (95% CI), months Immature 9.7(5.8-NE) 7.2(5.4-11.3) Immature HR / 0.67 / Any-G/G ≥3 TRAEs, % 100/94.4 100/82.4 100/75.0 100/100 100/87.0 100/85.7 100/73.3 100/75.0 *In pts with ≥1 post-baseline tumor assessment. PFS, progression-free survival; NE, not estimable; G, grade; TRAE, treatment-related adverse event.